Implantable medical devices such as tunneled catheters play a major role in general medicine. Within days of insertion, almost all central venous catheters are coated with a fibrin sheath, and within 30 clays, most catheter-related thrombi arise. (See C Harter, H J Salwender, A Bach, G Egerer, H Goldschmidt and A D Ho (2002) Catheter-related infection and thrombosis of the internal jugular vein in hematologic-oncologic patients undergoing chemotherapy: a prospective comparison of silver-coated and uncoated catheters. Cancer 94: 245-251.) Aside from reducing the function of the catheter, these catheter-related thrombi can cause postphlebitic syndrome in 15%-30% cases and pulmonary embolism in 11% of the cases. (See D J Kuter (2004) Thrombotic Complications of Central Venous Catheters in Cancer Patients. The Oncologist 9: 207-216.)
To minimize the risk of thrombosis, immobilization of fibrinolytic enzymes such as Urokinase (uPA) on the surface of implantable medical devices such as tunneled catheters has been described. Examples of immobilized fibrinolytic enzymes are disclosed in U.S. Pat. Nos. 4,305,926, 4,273,873, 4,378,435, and 5,380,299. Unfortunately, the fibrinolytic activity from such devices, e.g. urokinase coated hemodialysis catheter from Unitika (Blood access UK-catheter, Unitika), is retained for less than two weeks. This duration is insufficient for long term or chronic devices. A variety of agents have been conventionally utilized to stabilize fibrinolytic enzymes in solution. Examples of agents utilized to stabilize fibrinolytic enzymes in solution are disclosed in the following foreign patents: Japanese Patent No. JP61238732A2; European Patent No. EP0200966B1; Canadian Patent No. CA2579458AA; European Patent No. EP0391400 A2; and Japanese Patent No. JP55034082A2. However, to date, these agents have not been successfully utilized in an implantable medical device.
Accordingly, it is desirable to provide an implantable medical device having extended thrombolytic properties that is capable of overcoming the disadvantages described herein at least to some extent.